Obesity in humans has reached epidemic proportions and is associated with numerous health risks, including cardiovascular disease, diabetes mellitus, certain types of cancer, and reproductive defects. Abnormal weight regulation is also linked to abnormal eating behaviors (bulimia nervosa and binge eating disorder, anorexia nervosa) and common psychiatric diseases. To elucidate the molecular mechanisms underlying extreme obesity and related phenotypes, we will study unique large families with a very early-onset form of obesity, associated with hyperphagia and metabolic dysfunction. We have recently described seven generation pedigrees with extremely obese children and adults in human genetic isolates. We plan to identify genes underlying obesity and to elucidate the molecular pathway leading to both physiological and behavioral pathogenesis in food intake. The specific aims are as follows: 1) the chromosomal locus and mutant genes will be isolated for monogenic severe obesity in families found in the genetic isolate; 2) pathogenic features of abnormal protein and downstream elements of the cascade pathway leading to excessive fat accumulation will be identified; 3) the interaction of these elements with other signal transduction systems underlying reproductive and metabolic pathogenesis will be elucidated. Positional cloning and mutation analysis will be used to accomplish these goals. Tissue samples from affected homozygous individuals and asymptomatic relatives will be collected to investigate the biological effect of the mutant gene and protein. The mechanisms of resistance to leptin receptor mediated signaling in the obese individuals will be elucidated by analysis of gene expression, and in vitro assays for intracellular signaling in a mammalian cell model. Because obesity is a frequent disorder with high risk of morbidity and mortality, identification of candidate genes and their products will help elucidate control mechanisms of food intake and body mass, and make possible the development of diagnostic markers and specific pharmacological interventions.